Role of Chromatin Structural Changes in Regulating Human CYP3A Ontogeny. Drug Metab Dispos 2016 Jul;44(7):1027-37
Date
02/28/2016Pubmed ID
26921389Pubmed Central ID
PMC4931893DOI
10.1124/dmd.116.069344Scopus ID
2-s2.0-84975106004 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
Variability in drug-metabolizing enzyme developmental trajectories contributes to interindividual differences in susceptibility to chemical toxicity and adverse drug reactions, particularly in the first years of life. Factors linked to these interindividual differences are largely unknown, but molecular mechanisms regulating ontogeny are likely involved. To evaluate chromatin structure dynamics as a likely contributing mechanism, age-dependent changes in modified and variant histone occupancy were evaluated within known CYP3A4 and 3A7 regulatory domains. Chromatin immunoprecipitation using fetal or postnatal human hepatocyte chromatin pools followed by quantitative polymerase chain reaction DNA amplification was used to determine relative chromatin occupancy by modified and variant histones. Chromatin structure representing a poised transcriptional state (bivalent chromatin), indicated by the occupancy by modified histones associated with both active and repressed transcription, was observed for CYP3A4 and most 3A7 regulatory regions in both postnatal and fetal livers. However, the CYP3A4 regulatory regions had significantly greater occupancy by modified histones associated with repressed transcription in the fetal liver. Conversely, some modified histones associated with active transcription exhibited greater occupancy in the postnatal liver. CYP3A7 regulatory regions also had significantly greater occupancy by modified histones associated with repressed transcription in the fetus. The observed occupancy by modified histones is consistent with chromatin structural dynamics contributing to CYP3A4 ontogeny, although the data are less conclusive regarding CYP3A7. Interpretation of the latter data may be confounded by cell-type heterogeneity in the fetal liver.
Author List
Giebel NL, Shadley JD, McCarver DG, Dorko K, Gramignoli R, Strom SC, Yan K, Simpson PM, Hines RNAuthors
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of WisconsinKe Yan PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultAge Factors
Aged
Aged, 80 and over
Binding Sites
Child
Child, Preschool
Chromatin
Chromatin Assembly and Disassembly
Cytochrome P-450 CYP3A
Gene Expression Regulation, Developmental
Gene Expression Regulation, Enzymologic
Gestational Age
Hepatocytes
Histones
Humans
Infant
Liver
Middle Aged
Nucleic Acid Conformation
Promoter Regions, Genetic
Protein Conformation
Structure-Activity Relationship
Transcription, Genetic